Back
Tenofovir (TDF) is one of the most frequently used anti-retroviral drugs because of its excellent efficacy. However, long-term use of TDF has been associated with kidney tubular dysfunction (KTD). Although, the mechanism by which TDF causes kidney damage is yet to be fully elucidated. We therefore determine the association between polymorphisms in genes encoding drug transporters and KTD in adult Nigerian patients treated with TDF.
The association between TDF-induced KTD and 15 single nucleotide polymorphisms (SNPs) in the ABCC2, ABCC4, ABCC10, SCL22A6, SCL22A11 and ABCB1 genes was investigated in 800 Nigerian HIV-positive patients (400 with KTD and 400 without KTD) on long-term TDF treatment. KTD was diagnosed by the presence of at least 2 of the following abnormalities: non-diabetic glucosuria (urine glucose level ≥300 mg/dL daily); total excretion of phosphorus >1200 mg daily; fractional tubular resorption of phosphorus < 0.82; fractional excretion of uric acid > 15%; and proteinuria (> 0.2g/24hrs). The drug transporter gene SNPs were genotyped using Kompetitive allele-specific PCR (KASP™) technology at LGC Genomics Ltd. Associations between genotypes and KTD were tested by univariate and multivariate logistic regression analyses. For each SNP, the deviation of genotype frequencies from the Hardy-Weinberg equilibrium in controls was determined using a χ2 test.
Univariate analyses showed a significant association between KTD and ABCC2; rs2273697 genotype AG (odds ratio [OR], 1.394; 95% confidence interval [CI], 1.042–1.864; p = 0.025), ABCC10; rs9349256 genotype AG (OR, 2.380; 95% CI, 1.118–5.069; p = 0.025), and SLC22A11; rs11231809 genotype AT (OR, 1.671; 95% CI, 1.056–2.644; p = 0.028). In a multivariate analysis, after adjusting for age, gender, duration on tenofovir, body mass index and estimated glomerular filtration rate, ABCC2 genotype AG (adjusted OR, 1.427; 95% CI, 1.062–1.918; p = 0.018) and ABCC10 genotype AG (adjusted OR, 2.228; 95% CI, 1.036–4.790; p = 0.025) were independently associated with KTD. ABCC2; rs2273697 genotype GG (OR, 0.719; 95% CI, 0.541–0.857; p = 0.024), ABCC10; rs9349256 genotype GG (OR, 0.440; 95% CI, 0.206–0.943; p = 0.035), and SLC22A11; rs11231809 genotype TT (OR, 0.598; 95% CI, 0.378–0.947; p = 0.028) were protective for KTD.
We demonstrated that SNPs in ABCC2 and ABCC10 were independently associated with TDF-induced KTD in Nigeria patients. Close monitoring of tubular function is warranted in patients with ABCC2 rs2273697 G > A and ABCC10 rs9349256 G > A under TDF treatment.